Publications cited in this document are incorporated herein by reference.
This invention relates to the acetamide derivative modafinil. Modafinil (C15H15NO2S), is 2-(benzhydrylsulfinyl)acetamide, and is also known as 2-[(diphenylmethyl)sulfinyl]acetamide.
Modafinil has been described as presenting a xe2x80x9cneuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and of hypermotility; and by the absence of stereotypy (except in high doses) and of potentialisation of the effects of apomorphine and amphetaminexe2x80x9d (U.S. Pat. No. 4,177,290; hereinafter the xe2x80x9c""290 patent,xe2x80x9d which is incorporated herein by reference). A single administration of modafinil results in increased locomotor activity in mice and increased nocturnal activity in monkeys (Duteil et al., Eur. J. Pharmacol. 180:49 (1990)). The neuropsychopharmacological profile of modafinil has been distinguished from that of amphetamines (Saletu et al., Int. J. Clin. Pharm. Res. 9:183 (1989)). Modafinil is thought to modulate the central postsynaptic alpha1-adrenergic receptor, without participation of the dopaminergic system (Duteil et al., supra). Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy (Bastuji et al., Prog. Neuro-Psych. Biol. Psych. 12:695 (1988)).
Narcolepsy is a chronic disorder characterized by intermittent sleep attacks, persistent, excessive daytime sleepiness and abnormal rapid eye movement (xe2x80x9cREMxe2x80x9d) sleep manifestations, such as sleep-onset REM periods, cataplexy, sleep paralysis and hypnagogic hallucinations, or both (Assoc. of Sleep Disorders Centers, Sleep 2:1 (1979)). Most patients with narcolepsy also have disrupted nocturnal sleep (Montplaisir, in Guilleminault et al. eds., Narcolepsy, Spectrum Pub., New York, pp. 43-56). Pathological somnolence, whether due to narcolepsy or other causes, is disabling and potentially dangerous. Causes of pathological somnolence, other than narcolepsy, include chronic sleep loss (Carskadon et al., Sleep, 5:S73 (1982); Carskadon et al., Psychophysiology, 18:107 (1981)); sleep apnea (Kryger et al., Principles and Practice of Sleep Medicine, W. B. Saunders Co., Philadelphia, Pa. (1989)); and other sleep disorders (International Classification of Sleep Disorders: Diagnostic and Coding Manual, American Sleep Disorder Association, Rochester, Minn. (1990)). Whether due to narcolepsy or other causes, pathological somnolence produces episodes of unintended sleep, reduced attention, and performance errors. Consequently, it is linked to a variety of transportation and industrial accidents (Mitler et al., Sleep 11:100 (1988)). A therapeutic agent that reduces or eliminates pathological somnolence would have important implications not only for individual patients, but also for public health and safety.
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745 discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the treatment of Parkinson""s disease. The levorotatory form of modafinil, i.e., (xe2x88x92)benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression, hypersomnia and Alzheimer""s disease (U.S. Pat. No. 4,927,855). European Published Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-ischemic agent. European Published Application 594507 (published Apr. 27, 1994) discloses the use of modafinil to treat urinary incontinence.
Our invention discloses a pharmaceutical composition comprising modafinil in the form of particles of a defined size, and the use of such composition. We have discovered that the size of modafinil particles is important to the potency and safety profile of the drug.
xe2x80x9cParticle,xe2x80x9d as used herein, refers to an aggregated physical unit of the acetamide compound, i.e., a piece or a grain of acetamide. For example, FIGS. 2-5 provide photographic representations of various modafinil particles from Lots E-D and L-1.
As used herein, the term xe2x80x9cmean,xe2x80x9d when used in reference to the size of modafinil particles, refers to the sum of the size measurements of all measurable particles measured divided by the total number of particles measured. For example, for five measurable particles which could be measured, and were determined to have diameters of 20 microns, 23 microns, 20 microns, 35 microns and 20 microns, the mean diameter would be 23.6 microns. As used herein, the term xe2x80x9cdiameterxe2x80x9d is a volumetric measurement based on the presumed spherical shape of modafinil particles.
As used herein, the term xe2x80x9cmedian,xe2x80x9d when used in reference to the size of modafinil particles, indicates that about 50% of all measurable particles measured have a particle size less than the defined median particle size value, and that about 50% of all measurable particles measured have a particle size greater than the defined median particle size value. For example, for the five particle values listed above, the median diameter would be 20 microns.
As used herein, the term xe2x80x9cmode,xe2x80x9d when used in reference to the size of modafinil particles, indicates the most frequently-occurring particle size value. For example, for the five particle values listed above, the mode diameter would be 20 microns.
As used herein, the term xe2x80x9cpercent cumulative,xe2x80x9d when used in reference to the size of modafinil particles, refers to an aggregate of the individual percent values for all measurable particles measured at specified diameters.
As used herein, xe2x80x9caboutxe2x80x9d means plus or minus approximately ten percent of the indicated value, such that xe2x80x9cabout 20 micronsxe2x80x9d indicates approximately 18 to 22 microns. The size of the particle can be determined, e.g., by the methods provided below, and by conventional methods known to those of skill in the art.
In accordance with the invention disclosed herein, the mean particle size for a modafinil particle preferably ranges from about 2 microns to about 19 microns, more preferably from about 5 microns to about 18 microns, and most preferably from about 10 microns to about 17 microns.
In accordance with the invention disclosed herein, the median particle size for modafinil preferably ranges from about 2 microns to about 60 microns, more preferably from about 10 microns to 50 microns, and most preferably from about 20 microns to about 40 microns.
In accordance with the invention disclosed herein, the mode particle size for modafinil preferably ranges from about 2 microns to about 60 microns, more preferably from about 10 microns to about 50 microns, and most preferably from about 20 microns to about 40 microns.
We view the median measurement as having greater importance compared to the mode or mean values in that the median value provides an indication of the distribution of the particles measured in a given population. While not necessarily a limitation but rather an indicator of the consistency of the population measured, the ratio of median: mean: mode would ideally be 1:1:1; however, a ratio of median to mean of 1:2.50 to 1:0.50 is acceptable, and a ratio of median to mode of 1:2.50 to 1:0.50 is acceptable. Ideally, the standard deviation between the mean, median and mode measurements of a modafinil population would approach zero, indicating that every particle in the population measured was substantially identical or met the criteria for an ideal, normalized distribution. A standard deviation of less than about 25 between the mean, median and mode measurements is acceptable as an indication of the consistency of the population of the particles measured.
In accordance with the invention disclosed herein, it is preferable that not more than about 5% of the cumulative total (percent cumulative) of modafinil particles in any one dose provided to a mammal have particle sizes greater than about 200 microns; it is more preferable that not more than about 5% of the cumulative total (percent cumulative) of modafinil particles in any one dose provided to a mammal have particle sizes greater than about 190 microns; it is most preferable that not more than about 5% of the cumulative total (percent cumulative) of modafinil particles in any one dose provided to a mammal have particle sizes greater than about 180 microns. Thus, a xe2x80x9csubstantially homogeneous mixturexe2x80x9d of modafinil particles, as utilized herein, refers to a mixture of modafinil particles in which at least about 95% of the particles in that mixture are less than a defined size.
The value ranges defined above are based upon measurements made utilizing technology and instruments developed by the Hiac/Royko Division of Pacific Scientific (11801 Tech Road, Silver Spring, Md. 20904, United States of America). As those in the art may appreciate, different instruments manufactured by different companies may provide different measurements for the same particles. For example, in a characteristic modafinil lot (Lot L-2), the mean, median, and mode particle measurements obtained using a Coulter Counter TA II sizing counter were 43, 31, and 29 microns, respectively. Using a Hiac/Royko Model 9064 sizing counter, the mean, median and mode particle measurements obtained for Lot L-2 were 18.75, 31.41 and 25.31 microns, respectively. These differences are presumably predicated upon the different approaches used in measuring particles of such diminutive sizes. Thus, the value ranges provided above are relative and are most preferably to be considered in view of utilization of instruments and operating systems manufactured by Hiac/Royko, for example, and preferably, the Hiac/Royko Model 9064 system sizing counter.
Modafinil particles of the invention can be in the form of a pharmacologically acceptable salt, e.g., an acidic or basic addition salt.
In another aspect, the invention features a method of altering a somnolent state, e.g., narcolepsy, idiopathic hypersomnia and related sleep disorders, using modafinil particles of a defined size. The method involves administering to a mammal a pharmaceutical composition comprising an effective amount of modafinil in the form of particles of a defined size.
xe2x80x9cAn effective amountxe2x80x9d, as used herein, is an amount of the pharmaceutical composition that is effective for treating a somnolent or somnolescent state, i.e., an amount of modafinil of a defined particle size that is able to reduce or eliminate the symptoms of a somnolescent state. An effective amount of a pharmaceutical composition of the invention is useful for enhancing alertness, or increasing regularity of sleep rhythms.
A xe2x80x9cpharmaceutical compositionxe2x80x9d, as used herein, means a medicament for use in treating a mammal that comprises modafinil of a defined particle size prepared in a manner that is appropriate for administration to a mammal. A pharmaceutical composition according to the invention may also, but does not of necessity, include a non-toxic pharmaceutically acceptable carrier.
The pharmaceutical composition of the invention can contain at least about 50 mg, preferably at least about 100 mg, or more preferably at least about 200 mg of modafinil having a particle size as defined above. The pharmaceutical composition preferably contains no more than about 700 mg; more preferably, no more than about 600 mg; and most preferably, no more than about 400 mg, of modafinil having a particle size as defined above.
Other features and advantages of the invention will be apparent from the following detailed description and from the claims.